title: Neuroendocrine differentiation in acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor.
abstract: BACKGROUND
  Small cell lung cancer (SCLC) transformation during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer has been suggested as one of possible resistance mechanisms.
  
  
  METHODS
  We evaluated whether SCLC transformation or neuroendocrine (NE) differentiation can be found in the cell line model. In addition, we also investigated its effect on responses to conventional chemotherapeutic drugs of the SCLC treatment.
  
  
  RESULTS
  Resistant cell lines to various kinds of EGFR-TKIs such as gefitinib, erlotinib, CL-387,785 and ZD6474 with A549, PC-9 and HCC827 lung adenocarcinoma cell lines were established. Among them, two resistant cell lines, A549/GR (resistant to gefitinib) and PC-9/ZDR (resistant to ZD6474) showed increased expressions of CD56 while increased synaptophysin, Rb, p16 and poly(ADP-ribose) polymerase were found only in A549/GR in western blotting, suggesting that NE differentiation occurred in A549/GR. A549/GR cells were more sensitive to etoposide and cisplatin, chemotherapeutic drugs for SCLC, compared to parental cells. Treatment with cAMP and IBMX induced synaptophysin and chromogranin A expression in A549 cells, which also made them more sensitive to etoposide and cisplatin than parental cells. Furthermore, we found a tissue sample from a patient which showed increased expressions of CD56 and synaptophysin after development of resistance to erlotinib.
  
  
  CONCLUSIONS
  NE differentiation can occur during acquisition of resistance to EGFR-TKI, leading to increased chemosensitivity.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Chang
authors.forename: Seon Ye
authors.initials: SY
authors.lastname: Kim
authors.forename: Yun Jung
authors.initials: YJ
authors.lastname: Choi
authors.forename: Kwang Sup
authors.initials: KS
authors.lastname: So
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Rho
authors.forename: Woo Sung
authors.initials: WS
authors.lastname: Kim
authors.forename: Jae Cheol
authors.initials: JC
authors.lastname: Lee
authors.forename: Jin-Haeng
authors.initials: JH
authors.lastname: Chung
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Choi
keywords: Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Small Cell Lung Carcinoma